Two-component pharmaceutical composition for the treatment of pain

ABSTRACT

The present invention is directed to a pharmaceutical composition that includes a combination of about 2-5 milligrams of a non-steroidal anti-inflammatory drug and from about 2-30 milligrams of an opioid analgesic in a single pharmaceutical dosage unit that can provide effective chronic pain management with the added benefit of reduced side effects such as withdrawal and gastrointestinal disorders. The non-steroidal anti-inflammatory drug may be piroxicam and the opioid analgesic may be buprenorphine. The present invention also provides for a method of managing pain in a patient that includes administering the pharmaceutical composition previously described. The pharmaceutical composition previously described may be administered in a single or multiple dosage regimen.

CROSS REFERENCE TO RELATED APPLICATION

This is a continuation of U.S. application Ser. No. 11/152,642incorporated by reference in its entirety.

The invention relates generally to a pharmaceutical dosage unit having atherapeutically effective amount of a non-steroidal anti-inflammatorydrug in combination with a therapeutically effective amount of an opioidanalgesic that can be used for the treatment of pain with reduced sideeffects such as opioid withdrawal and gastrointestinal irritation anddamage. More particularly, the pharmaceutical dosage unit includespiroxicam in combination with buprenorphine for sublingualadministration.

BACKGROUND OF THE INVENTION

Pain is prevalent. It is estimated that more than 50 million Americanslive with chronic pain caused by various diseases or disorders, and eachyear nearly 25 million people suffer with acute pain as a result ofinjury or surgery. Furthermore, chronic pain has been said to be themost costly health problem in America. Estimated annual costs, includingdirect medical expenses, lost income, lost productivity, compensationpayments, and legal charges are currently about $90 billion. And thenumbers are rising. Estimates indicate that by 2030, 148 million peoplewill have chronic conditions, and associated annual direct costs willrise to $798 billion. Thus, pain management has been identified as oneof the most difficult challenges for the health care industry.

Non-steroidal anti-inflammatory drug NSAIDs (also referred to asnon-narcotic analgesics) are administered for the treatment of mild tosevere pain and in some instances are prescribed for continuous use inthe treatment of acute or chronic inflammatory states such as rheumatoidarthritis and osteoarthritis. NSAIDs are well absorbed following oraladministration but there is a high potential for adverse side-effectssuch as ulcerations, abdominal pain, cramping, nausea, gastritis, kidneydisease, angiodema, pancreatitis, and even serious gastrointestinalbleeding and liver toxicity at the upper limits of their effective doseranges. Thus, the ability to use higher dosages of NSAIDs is generallylimited. Moreover, above each NSAIDs' upper limit or ceiling,administration of additional NSAID or use of combinations of NSAIDs doesnot usually increase the analgesic or anti-inflammatory effect.

Opioid analgesics (also referred to as narcotic analgesics) such asbuprenorphine are often used when pain control with NSAIDs isineffective. While narcotic analgesics vary considerably in theirchemical structures and pharmacological properties, almost all sufferthe disadvantages of tolerance and possible addiction with continuedusage.

Narcotic analgesics are classified generally as narcotic agonists ornarcotic antagonists. Drugs that activate receptors in the brain aretermed agonists. Hence, a drug that activates an opioid receptor istermed an opioid agonist. The repeated administration of opioid agonistsresults in dose-dependent physical dependence and tolerance. Physicaldependence manifests as a characteristic set of withdrawal signs andsymptoms upon reduction, cessation, or loss of an active compound at anopioid receptor. These withdrawal signs and symptoms can includesweating, cramps, aches, lacrimation, diarrhea, rhinorrhea,piloerection, and pupillary dilation. A drug that binds to a receptor inthe brain to block the receptor rather than activate it is termed anantagonist. Examples of opioid antagonists are naltrexone and naloxone.Partial agonists are drugs that activate receptors in the brain but notto the extent as full agonists. Buprenorphine is an example of a partialagonist (also referred to as a partial opioid agonist or opioidanalgesic). It is the partial agonist properties of buprenorphine thatcontribute to its effectiveness in pain management and provide the addedbenefit of reduced dependence on and/or addiction to opioids. Consistentwith its agonist action at opioid receptors, however, partial agonistssuch as buprenorphine are still abusable, particularly by individualswho are not already physically dependents on opioids.

Although NSAIDs and opioid analgesics are individually limited in theirability to effectively manage pain without inducing adverse side effectssuch as gastrointestinal disorders, dependence and/or addiction to, andwithdrawal upon cessation or reduction, it has now been found that apharmaceutical composition for sublingual administration havingrelatively low effective amounts of a NSAID such as piroxicam incombination with relatively high effective amounts of an opioidanalgesic such as buprenorphine improves upon existing pain medicationsand provides the additional benefit of reduced side effects.

SUMMARY OF THE INVENTION

The present invention is directed to a pharmaceutical composition thatincludes a combination of a non-steroidal anti-inflammatory drug such aspiroxicam and an opioid analgesic such as buprenorphine in apharmaceutical dosage unit that provides safe and effective painmanagement with the added benefit that side effects such asgastrointestinal tract damage and withdrawal as a result of physicaldependence and/or addiction are reduced. In one embodiment, theinvention is a pharmaceutical combination of a low effective amount ofpiroxicam and a high effective amount of buprenorphine. In anotherembodiment, the pharmaceutical composition is a combination of about 2-5milligrams of a non-steroidal anti-inflammatory drug such as piroxicamand about 2-30 milligrams of an opioid analgesic such as buprenorphinefor sublingual administration.

The present invention also provides for a method of managing pain withreduced side effects in a patient that includes administering to thepatient, in a single or multiple dosage regime, the pharmaceuticalcomposition previously described.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

The present invention is a pharmaceutical composition for managing painthat includes a combination of a non-steroidal anti-inflammatory drug(“NSAID”) and an opioid analgesic in a single pharmaceutical dosageunit. As used herein, pain management includes the pain treatment andpain control. The present invention offers advantages over existing painmanagement compositions that include opioid analgesics and NSAIDs byproviding safe and effective pain management with a reduction in sideeffects such as gastrointestinal tract damage and withdrawal as a resultof physical dependence on and/or addiction to the opioid analgesic. Inone embodiment of the present invention, the pharmaceutical compositionis a combination of a NSAID such as piroxicam and an opioid analgesicsuch as buprenorphine in a single pharmaceutical dosage unit. In oneembodiment, the pharmaceutical dosage unit may be administeredsublingually.

NSAIDs vary widely in their chemical structure and in their biologicalprofiles as analgesics, anti-inflammatory agents and anti-pyreticagents. Aspirin, acetaminophen and phenacetin have long been among themost commonly used NSAIDs. Other examples of NSAIDs for use in thepresent invention include ibuprofen, diclofenac, naproxen, benoxaprofen,flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen,carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen,aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin,sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin,fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid,flufenamic acid, niflumic acid tolfenamic acid, diflunisal, flufenisal,piroxicam, meloxicam, sudoxicam or isoxicam, and mixtures thereof. Amongthe newer NSAID compounds are diflunisal (DOLOBID), ibuprofen (BRUFEN),naproxen (NAPROSYN), fenoprofen (FENOPRON), piroxicam (FELDENE),flurbiprofen, mefenamic acid (PONSTAN) and sulindac (CLINORIL). In oneembodiment of the present invention, the NSAID is indomethacin,meloxican, ketoprofen, piroxicam, or combinations thereof. In aparticular embodiment of the present invention the NSAID is piroxicam.

Piroxicam is4-hydroxyl-2-methyl-N-2-pyridinal-2H-1,2-benzothiazine-3-carboximide1,1-dioxide. Piroxicam occurs as a white crystalline solid that issoluble in alcohol and aqueous solutions and sparingly soluble in water,dilute acid and most organic solvents. Piroxicam exhibits a weaklyacidic 4-hydroxy proton (pKa 5.1) and weakly basic pyridyl nitrogen (pKa1.8). Piroxicam is available commercially as FELDENE in 10 mg and 20 mgcapsules from Pfizer Inc., distributed by Pfizer Labs, New York, N.Y.Piroxicam has the molecular formula C₁₅H₁₃N₃O₄S and the followingstructural formula:

NSAIDs such as piroxicam generally possess anti-inflammatory,antipyretic and analgesic activities. The exact mechanism of action ofNSAIDs and the relationship between chemical structure and analgesic,anti-inflammatory and anti-pyretic effect are not yet fully understood,but these properties may be mediated through the inhibition ofprostaglandin synthesis. More specifically, NSAID compounds have beenshown to be inhibitors of either or both of cyclooxygenase I (COX I) orcyclooxygenase II (COX II), which are involved in the synthesis ofprostaglandins. Induction of the synthesis of COX II is associated withinflammatory processes and inhibition of COX II may result in theantipyretic and anti-inflammatory properties of NSAID compounds.Inhibition of constitutively-synthesized COX I may be associated withundesirable side effects such as gastric ulcers. Accordingly, selectiveinhibition of COX II rather than COX I may offer a therapeuticadvantage.

While piroxicam is available for oral administration as FELDENE in 10 mgor 20 mg dosage units and is typically administered in amounts of 20 mgdaily, the present invention is directed to relatively lower amounts(low effective amount) of NSAIDs such as piroxicam compared to thedosage amounts typically administered for pain management. Thus, as usedherein, relatively low amount includes dosage amounts at about or below5 mg. In one embodiment of the present invention, the NSAID is presentin an amount of about 2-5 mg. In another embodiment, the NSAID ispresent in an amount of about 2-3 mg. In yet another embodiment of thepresent invention, the NSAID is present in an amount of about 2.5 mg. Instill another embodiment, the NSAID is present in an amount of about 2mg. Additionally, the NSAID of the present invention may be administeredsublingually for absorption through mucous membranes in mouth. The loweffective amount and sublingual administration of the NSAID may decreasethe risk of side effects such as gastrointestinal disorders. In oneembodiment, the side effects are gastrointestinal ulceration, abdominalpain, cramping, nausea, gastritis, kidney disease, angiodema,pancreatitis, gastrointestinal bleeding, liver toxicity, or combinationsthereof.

Opioid analgesics also vary widely in their chemical structure and intheir biological profiles. Presently known opioid analgesics includealfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,cyclazocine, desomorphine, dextromoramide, dezocine, diampromide,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazenefentanyl; heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone,metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine,norlevorphanol, normethadone, nalorphine, normorphine, norpipanone,opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone,phenomorphan, phenazocine, phenoperidine, piminodine, piritramide,propheptazine, promedol, properidine, propiram, propoxyphene,sufentanil, tramadol, tilidine, salts thereof and mixtures thereof. In aparticular embodiment of the present invention the opioid analgesic isbuprenorphine.

Buprenorphine, a thebaine derivative that is legally classified as anarcotic, is17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl-6,14-ethenomorphian-7-methanol.Buprenorphine generally occurs as a white powder that is weakly acidicwith limited solubility in water. Buprenorphine HCl has the molecularformula C₂₉H₄₁NO₄HCl and the following structural formula:

Buprenorphine is available commercially for parenteral administrationunder the name BUPRENEX (buprenorphine hydrochloride) from ReckittBenckiser, Richmond, Va., and generically as buprenorphine from AbbottLaboratories. Buprenorphine is also available in sublingual tabletsSUBUTEX (buprenorphine HCl) and SUBOXONE (buprenorphine HCl/naloxone HCldihydrate) both available from Reckitt Benckiser.

Buprenorphine has poor oral and/or gastrointestinal bioavailability thusbuprenorphine is usually given by injection, via a sublingual tablet, oras a transdermal patch. Abuse of buprenorphine has been reported tooccur via the sublingual and intranasal routes but primarily viadiversion of sublingual tablets to the injection route. Therefore,formulations of buprenorphine for opioid addiction and dependencytreatment are generally in the form of sublingual tablets such asSUBUTEX and SUBOXONE.

The typical analgesic dose of buprenorphine is relatively low at amountsof 0.3-0.6 mg when injected (intramuscular or intravenous). Because thebioavailability of buprenorphine is less when administered orally orsublingually as compared to injections of buprenorphine, sublingualtablets are available in increased dosages of 2 mg or 8 mg. The presentinvention, however, may include a relatively high amount (high effectiveamount) of an opioid analgesic such as buprenorphine in a pharmaceuticaldosage compared to dosages typically administered for pain management.In one embodiment, relatively high amount includes dosage amountsgreater 0.6 mg of buprenorphine when injected or 8 mg of buprenorphinewhen administered as a sublingual tablet. Thus, in one embodiment of thepresent invention, an opioid analgesic such as buprenorphine is presentin an amount of about 2-30 mg. In another embodiment, the opioidanalgesic is present in an amount of about 10-30 mg. In still anotherembodiment, the opioid analgesic is present in an amount of about 10-15mg.

Lower dosages of opioid analgesics such as buprenorphine are alsoeffective in the present invention, however, particularly whenadministered in combination with a NSAID such as piroxicam. NSAIDs suchas piroxicam have a prolonged half-life (approximately 50 hours), whichresults in the maintenance of relatively stable plasma concentrationsthroughout the day on once daily doses and to significant accumulationupon multiple dosing. Opioid analgesics such as buprenorphine also havean unusually long half-life (approximately 36 hours). As such, theseNSAIDs and opioid analgesics may be combined in a single pharmaceuticaldosage unit as a pharmaceutical combination dosage unit to provide safeand effective pain management with a reduction in side effects such asgastrointestinal tract damage and withdrawal as a result of physicaldependence on and/or addiction to the opioid analgesic. Thispharmaceutical combination dosage unit may include a low effectiveamount of a NSAID such as piroxicam and a high effective amount of anopioid analgesic such as buprenorphine where low effective amount of anNSAID is less than about 5 mg and high effective amount of an opioidanalgesic is about 2-30 mg. Thus, in one embodiment, a NSAID such aspiroxicam is present in an amount of about 2-5 mg and an opioidanalgesic such as buprenorphine is present in an amount of about 2-30mg. In another embodiment, the NSAID is present in an amount of about2-3 mg and the opioid analgesic is present in an amount of about 2-15mg. In still another embodiment, the pharmaceutical dosage combinationincludes about 2.5 mg of an NSAID and about 2 mg of an opioid analgesic.

The pharmaceutical dosage units of the present invention may beformulated for various forms of administration, including, for example,sublingual, mucosal, parenteral, intravenous, intramuscular, and/ortransdermal administration and combinations thereof. Consistent with thevarious forms of administration, the pharmaceutical dosage unit cangenerally be formulated, for example, as a tablet, capsule, injection,and/or patch. In one embodiment of the present invention, the NSAID andopioid analgesic are combined in the same formulation of thepharmaceutical dosage unit. In another embodiment of the presentinvention, the NSAID and opioid analgesic are provided as individualformulations of the pharmaceutical dosage unit but administered suchthat the active ingredients are delivered to the patient simultaneously.In a particular embodiment of the present invention, the NSAID andopioid analgesic are combined in a sublingual tablet to be placed withinthe mouth and/or under the tongue.

Sublingual tablets are designed to dissolve very rapidly. Examples ofsuch formulations include ergotamine tartrate, isosorbide dinitrate,isoproterenol HCl. The necessary ingredients for the pharmaceuticaldosage unit may be processed in accordance with known methods, using orincorporating familiar coatings and additives as required. By way ofexample only, in addition to the pharmaceutically active components, adosage unit may contain effective amounts of binders, fillers,disintegrants, sustained-release agents, diluents, anti-adherents,glidants, flow aids, plasticizers and lubricants, which are well knownin the field of pharmaceutical processing. For instance, the formulationof these tablets may contain, in addition to the active agents, alimited number of soluble excipients, including a binder such aspovidone or hydroxypropyl methylcellulose (HPMC), diluents such aslactose, mannitol, starch or cellulose, a disintegrant such aspregelatinized or modified starch, lubricants such as magnesiumstearate, stearic acid or hydrogenated vegetable oil, a sweetener suchas saccharin or sucrose and suitable flavoring and coloring agents. Theprocess of making sublingual tablets generally involves moistening theblended powder components with an alcohol-water solvent systemcontaining approximately 60% alcohol and 40% water and pressing thismixture into tablets.

A particular tablet-form formulation in accordance with theabove-described embodiment of the present invention includes thefollowing components:

-   Buprenorphine: 2 mg/tablet;-   Piroxicam: 5 mg/tablet;-   Sugar Base A: qs to desired tablet weight of approximately 215 mg;    and-   Coloring: 20 mg per 150 tablets,    where Sugar Base A includes the following components given by    approximate wt.-% of Sugar Base A: DiPac (tableting sugar) 77 wt.-%,    lactose 7 wt.-%, microcrystalline cellulose 5 wt.-%, flavoring 5    wt.-%, CrosPovidone 5 wt.-%, and magnesium stearate 1 wt.-%.

In an alternative tablet-form formulation, Naloxone is added to theformulation. Naloxone is an opioid antagonist that binds to a receptorin the brain to block the receptor rather than activate it. Thus, insome instances the inclusion of Naloxone may reduce opiate tolerance oreven partially reverse tolerance if it occurs. Accordingly, Naloxone maybe included to further reduce the abuse potential of the pharmaceuticaldosage unit and withdrawal as a result of physical dependence and/oraddiction. In this embodiment, the following components are included:

-   Buprenorphine: 2 mg/tablet;-   Piroxicam: 5 mg/tablet;-   Naloxone: 0.2 mg/tablet-   Sugar Base A: qs to desired tablet weight of approximately 215 mg;    and-   Coloring: 20 mg per 150 tablets,    where Sugar Base A includes the following components given by    approximate wt.-% of Sugar Base A: DiPac (tableting sugar) 77 wt.-%,    lactose 7 wt.-%, microcrystalline cellulose 5 wt.-%, flavoring 5    wt.-%, CrosPovidone 5 wt.-%, and magnesium stearate 1 wt.-%.

The pharmaceutical dosage unit may be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. In one embodiment, thepharmaceutical dosage unit may be formulated such that a singlesublingual tablet is administered twice daily. In one embodiment,pharmaceutical dosage unit of the present invention once in the morning,such as at 8:00 am, and then again six hours later in the earlyafternoon or at approximately 2:00 pm.

Alternatively, the pharmaceutical dosage unit may formulated so that theactive ingredients (i.e. the NSAID and the opioid analgesic) exhibitsustained-release characteristics upon administration to the patient.For example, the active ingredients may be delivered with an oralmucosal patch. Methods of making such patches are well known to one ofskill in the art. In one embodiment the oral mucosal patch is preparedby homogeneously mixing buprenorphine and piroxicam with appropriateamounts of Carbopol 934, polyisobutylene, and polyisoprene using atwo-roll mill and then compressing the mixture to the appropriatethickness. A membrane backing such as ethylcellulose is then applied toone side of the compressed material and circular disks, having an areaof about 0.5 cm² and thickness of about 0.6 mm for example, may bepunched from the material. The backing inhibits drug release from oneside of the disk and reduces adhesion to opposing side tissues. The oralmucosal patches may be secured to mucosal buccal surfaces such as thegums, lips, and cheeks, and worn for extended periods. In one instance,the oral mucosal patches may be work for about 12 hours.

In another sustained release embodiment, the active ingredients may bedelivered using a tablet-form dosage unit having a partially hydrophilicmatrix which exhibits sustained release of at least one of the activecomponents. In addition to the active ingredients, the tablet iscomprised of, for example, ethylcellulose as a sustained-release agentand hydroxypropyl methylcellulose (HPMC) as a film former. Further,bulking agents such as microcrystalline cellulose and starch, apolyvinylpyrrolidone binder, silicon dioxide as an anti-adherent,dibutyl sebacate as a plasticizer, and magnesium stearate as a lubricantmay be included. Using conventional processes, the listed ingredients,other than ethylcellulose, HPMC and dibutyl sebacate, are combined andpressed into a tablet. The tablet is then coated with theethylcellulose, HPMC and dibutyl sebacate prior to administration of thetablet. When this tablet encounters an aqueous environment, such as themucosal buccal surfaces, portions of the tablet coating dissolve,leaving a non-continuous film of water-insoluble ethylcellulosesurrounding the remaining tablet core. The rate of diffusion of theactive ingredients from the tablet core into the aqueous environment isdetermined by the concentration of ethylcellulose, HPMC and dibutylsebacate in the coating.

As used in this specification and in the claims, the phrase “sustainedrelease” indicates that an active component is released from the dosageunit over a period of time which is longer than its ordinary in vivohalf-life, thus extending the presence of the component in a patient'ssystem considerably beyond its ordinary half-life. Under suchcircumstances, the active component is said to “exhibitsustained-release characteristics.” In contrast, the phrase “immediaterelease” indicates that an active component is released from the dosageunit within a short period of time (i.e., much shorter than its ordinaryin vivo half-life); and decrease in concentration of the activecomponent over time will be approximately described by its ordinaryhalf-life. Under such circumstances, the active component is said to“exhibit immediate-release characteristics.” In compositions of thepresent invention having more than one active component that is intendedto exhibit sustained-release characteristics, an important considerationis that the release rate of each active component will need to beseparately customized to produce the desired release profile, since thecomponents will have different in vivo half-lives.

Another aspect of the present invention is a method of managing pain,the method including administering a pharmaceutical dosage unit havingabout 2-5 mg of a NSAID such as piroxicam in combination with about 2-30mg of an opioid analgesic such as buprenorphine. The NSAID and opioidanalgesic may be administered sublingually as a single pharmaceuticaldosage unit or simultaneously in separate, sublingual pharmaceuticaldosage units. In one embodiment, the pharmaceutical dosage unit is asublingual tablet to be placed under the tongue.

The present invention also provides for a method of treating pain withreduced side effects, the method including administering apharmaceutical dosage unit having about 2-5 mg of a NSAID such aspiroxicam in combination with about 2-30 mg of an opioid analgesic suchas buprenorphine. The NSAID and opioid analgesic may be administeredsublingually as a single pharmaceutical dosage unit or simultaneously inseparate, sublingual pharmaceutical dosage units. In one embodiment theside effects may include opioid withdrawal. Alternatively, the sideeffects may include, for example, ulcerations, abdominal pain, nausea,liver toxicity, gastrointestinal bleeding, kidney disease, orcombinations thereof.

The present invention further provides a method of treating withdrawal,the method including administering a pharmaceutical dosage unit havingabout 2-5 mg of a NSAID such as piroxicam in combination with about 2-30mg of an opioid analgesic such as buprenorphine. The NSAID and opioidanalgesic may be administered sublingually as a single pharmaceuticaldosage unit or simultaneously in separate, sublingual pharmaceuticaldosage units. In one embodiment, the pharmaceutical dosage unit is asublingual tablet to be placed under the tongue.

The appropriate dosages for administration to a patient for any of thecompositions or methods of the present invention should be determined inaccordance with accepted guidelines, such as those given by thePhysician's Desk Reference. The patient's response to the pharmaceuticalcomposition of the present invention may be monitored and the dosageadjusted as necessary.

The present invention is also directed to a method of treating pain in ahuman patient that includes administering to the human patient, in asingle or multiple dosage regimen, a pharmaceutical dosage unit, wherethe dosage unit includes about 2-5 mg of a NSAID such as piroxicam incombination with about 2-30 milligrams of an opioid analgesic such asbuprenorphine. The NSAID and opioid analgesic may be administeredsublingually as a single pharmaceutical dosage unit or simultaneously inseparate, sublingual pharmaceutical dosage units. In one embodiment, thepharmaceutical dosage unit is a sublingual tablet to be placed under thetongue. The method may additionally include monitoring the human patientto determine if the dosage regime is appropriate and either increasingor decreasing the dosage regimen as necessary.

The present invention offers significant advantages to patients alreadyusing high dosages of opioids, to patients seeking pain managementmethods to treat chronic pain without side effects or long term effects,and to patients seeking opioid addiction treatment. The presentinvention also provides physicians and patients an ability to switchfrom the present invention to a different pain management prescriptionwithout withdrawal issues.

Further objects and advantages of the invention will become apparentfrom a consideration of the examples and ensuing description whichillustrate embodiments of the invention, it being understood that theforegoing statements of the objects of the invention are intended togenerally explain the same without limiting it in any manner.

EXAMPLES Example 1

Patients taking 15-80 mg/day of hydrocodone or 40-320 mg/day ofoxycontin were switched to a pharmaceutical dosage unit including 2.5 mgpiroxicam and 2 mg buprenorphine in a sublingual tablet. The sublingualtablets were administered to each patient twice daily. The patientsperceived pain was measured using a visual analog scale (VAS).

Patients formerly taking 15-80 mg/day of hydrocodone experienced a 21%decrease in perceived pain scores after conversion. The perceived painscores also remained stable when ½ dose reduction was attempted after a22 day stabilization phase.

Patients that had been taking 40-320 mg/day of oxycontin experienced a27% reduction in perceived pain 72 hours after conversion. No withdrawalor parasympathetic symptoms were noted in the oxycontin patients. Theperceived pain scores remained stable when dose reduction was attemptedafter a 40-day stabilization phase.

The patients also generally reported feelings of being more in controlof their lives, thinking clearer, sleeping better and being lesslethargic than when they were taking hydrocodone or oxycontin.

Example 2

Patients taking 20-140 mg/day of methadone were also switched to apharmaceutical dosage unit including 2.5 mg piroxicam and 2 mgbuprenorphine in a sublingual tablet. These patients took an average of6 days to convert before withdrawal was completely eliminated.

Patients taking 20-50 mg/day of methadone converted without ill effects,but did not take methadone the first day.

Patients taking 50-140 mg/day of methadone were first titrated down withUltram (2-3 tablets every 4 hrs) for four days. Following this period,patients were given injections containing 0.03 mg buprenorphine and 60mg torodol to see if further time was needed before the sublingualtablets containing buprenorphine and piroxicam could be started withoutrisk of precipitating withdrawal. Significant withdrawal was observed in18% of the patients on the first day the sublingual tablets wereadministered. Stomach tightness, nausea, and restless legs were the mostcommon complaints from these patients. None of the patients experiencedwithdrawal on the second day the sublingual tablet was administered.

Pain scores using a VAS did not improve until week 2 with the methadonepatients. By week 4, the methadone patients were willing to titrate downand by week 6 there was significant improvement in the VAS and nodifference was noted with methadone and other opiate tolerant groupsafter the 6th week.

Example 3

Patients that had been taking piroxicam were also switched to apharmaceutical dosage unit including 2.5 mg piroxicam and 2 mgbuprenorphine in a sublingual tablet. The patients reported a 50%reduction in GI upset compared to when they were taking piroxicamorally.

The particular embodiments disclosed above are illustrative only, as theinvention may be modified and practiced in different but equivalentmanners apparent to those skilled in the art having the benefit of theteachings herein. Furthermore, no limitations are intended to thedetails of construction or design herein shown, other than as describedin the claims below. It is therefore evident that the particularembodiments disclosed above may be altered or modified and all suchvariations are considered within the scope and spirit of the invention.Accordingly, the protection sought herein is as set forth in the claimsbelow.

What is claimed is:
 1. A pharmaceutical formulation consistingessentially of piroxicam or meloxicam of 5 milligrams or less andbuprenorphine of 2-30 milligrams, and a pharmaceutically acceptableexcipient for reduction of chronic pain with reduced side effects. 2.The pharmaceutical formulation of claim 1, wherein the reduced sideeffect is gastrointestinal ulceration, abdominal pain, cramping, nausea,gastritis, kidney disease, angiodema, pancreatitis, gastrointestinalbleeding, liver toxicity, or combinations thereof.
 3. The pharmaceuticalformulation of claim 1, formulated for sublingual, mucosal, parenteral,intravenous, intramuscular, transdermal administration and combinationsthereof.
 4. The pharmaceutical formulation of claim 1, whereinbuprenorphine is present in an amount of 2-15 milligrams.
 5. Thepharmaceutical formulation of claim 1, wherein buprenorphine is presentin an amount of 2 milligrams.
 6. A method of reducing chronic pain in apatient comprising administering to the patient, in one or more doses ofa single pharmaceutical formulation consisting essentially of 2-5milligrams of piroxicam or meloxicam and 2-30 milligrams ofbuprenorphine, and a pharmaceutically acceptable excipient.
 7. Themethod of claim 6, wherein piroxicam is present in an amount of 2-3milligrams and buprenorphine is present in an amount of 2-15 milligrams.8. The method of claim 6, wherein piroxicam is present in an amount of2.5 milligrams and buprenorphine is present in an amount of 2milligrams.
 9. The method of claim 6, wherein administering thepharmaceutical formulation comprises sublingually, mucosally,parenterally, intravenously, intramuscularly, transdermally andcombinations thereof, to the subject.
 10. The method of claim 6, whereinthe pharmaceutical formulation reduces pain with reduced side effects.11. The method of claim 10, wherein the side effect is gastrointestinalulceration, abdominal pain, cramping, nausea, gastritis, kidney disease,angiodema, pancreatitis, gastrointestinal bleeding, liver toxicity, orcombinations thereof.
 12. The method of claim 10, wherein the reducedside effect is opioid withdrawal symptoms.
 13. The pharmaceuticalformulation of claim 6, wherein the patient has opioid tolerance.